Metolazone, 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolin esulfonamide, is a potent antihypertensive and diuretic drug which is widely available in oral dosage forms. In hospital and other critical care situations it is desirable to have available an injectable form of the drug , for example, in the case of refractory edema or renal failure. Aqueous solutions are preferred for parenteral dosage forms, however, metolazone is virtually insoluble in water (0.02 mg/mL) and thus achieving an effective concentration in a volume of water suitable for parenteral administration is not practical.
Drug substances which are insoluble in water may be solubilized by alternative methods. Where the drug substance possesses acidic or basic functional groups salt formation with pharmaceutically acceptable bases or acids is possible. Salts are usually more soluble in water than the free drug substance because of their ionic nature. Metolazone possesses an acidic sulfonamide group capable of forming salts with strong bases, for example, alkali hydroxides such as sodium or potassium hydroxides. The sodium salt of metolazone is quite soluble in aqueous sodium hydroxide solutions, however a pH of 11.0 is required to maintain solution. Parenteral administration of solutions at pH 11 frequently causes irritation at the site of injection which may be due to the high pH or to precipitation of the drug. Unfortunately the stability of metolazone in such an aqueous solution is poor and degradation of the metolazone is observed. A parenteral formulation of metolazone comprising a lyophilized solid prepared from the sodium salt of metolazone and sodium hydroxide is more stable but reconstitution of the solid with water still requires a pH of about 11. Reconstitution of drug compositions requires extra steps, is prone to error and is generally considered inconvenient by physicians and nurses.
Ready made solutions are more desirable as parenteral formulations and solutions of water-insoluble drug substances in suitable solvents or mixtures of such solvents may provide an alternative method of obtaining an acceptable parenteral formulation, especially if the problems of irritation and/or precipitation at the site of injection are also overcome. It is usually desirable to administer as low a total volume of the injectable solution as possible in order to minimise the side effects due to the solvent. Consideration must also be given to the risk of precipitation of the drug when the solution is diluted in realistic proportions with other infusion solutions. Precipitation upon intravenous injection can result in erratic or reduced drug bioavailability, pain upon injection and/or phlebitis.
Among the cosolvent mixtures which are acceptable for pharmaceutical parenteral formulations are aqueous mixtures with one or more of propylene glycol, ethanol, benzyl alclohol, polyethylene glycols and castor oil in various proportions. Ethanol may be used in the form of absolute alcohol or aqueous ethanol (95%). Polyethylene glycol 300 and polyethylene glycol 400 are preferred liquid forms of polyethylene glycol.
Important criteria for a cosolvent parenteral formulation of metolazone are that (a) the solvent mixture be acceptable, (b) the volume be minimized so that the daily administration does not exceed a practical volume of about 20 mL, (c) precipitation of the drug substance at the site of injection be negligible.
Precipitation at the site of injection is related to the solubility of the drug in the aqueous biological fluids. The rate of administration of the solution of the drug substance determines the degree of dilution in biological fluids and whether the solubility of the drug in the mixture of fluids will be exceeded. Normally one would expect that if the concentration of the drug at the site of injection exceeds the solubilty of the drug in the biological fluid precipitation would occur.